In vivo efficacy of marimastat and chemoradiation in head and neck cancer xenografts.
OBJECTIVE
To assess the effect of combining a synthetic matrix metalloprotease inhibitor and chemoradiation therapy on tumor growth in a murine model of head and neck squamous-cell carcinoma (SCC).


METHODS
Athymic, nude mice bearing SCC-1 xenografts were used to comprise 4 treatment groups: (1) control receiving vehicle alone, (2) marimastat alone, (3) cisplatin + radiation in combination and (4) marimastat + cisplatin + radiation in combination. The marimastat was administered at a dose of 8.7 mg/kg/day over a 14-day period via a subcutaneous osmotic pump. The control group received vehicle only via a subcutaneous osmotic pump. Radiotherapy was given in 4 fractions of 8 Gy divided over days 8, 12, 16 and 20 with 4 intraperitoneal doses of cisplatin (3 mg/kg) 1 h before each fraction of radiation.


RESULTS
Animals receiving triple treatment had delayed growth, measured as lengthened tumor doubling time, compared to the cisplatin + radiation combination (p = 0.03). Also, compared to control, the triple-treatment group (p = 0.005) had delayed growth in terms of doubling time. Factor VIII immunohistochemistry to assess microvessel density did not demonstrate a reduction in neovascularization between the triple-treatment and cisplatin + radiation combination groups. Statistical analysis failed to demonstrate any significant difference among groups.


CONCLUSIONS
Chemoradiation + marimastat therapy had delayed tumor growth, compared to the chemoradiation alone. Based on these results, marimastat may work in combination with chemotherapy and radiation to inhibit tumor growth.
Skipper
Joni B
JB
Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
McNally
Lacey R
LR
Rosenthal
Eben L
EL
Wang
Wenquan
W
Buchsbaum
Donald J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002945:Cisplatin / Q000627:therapeutic use*; D005260:Female; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects / Q000528:radiation effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D011480:Protease Inhibitors / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C100342:marimastat; D002945:Cisplatin